Véronique Alphand

Towards large-scale synthetic applications of Baeyer-Villiger monooxygenases

Biocatalysis is coming of age, with an increasing number of reactions being scaled-up and developed. The diversity of reactions is also increasing and oxidation reactions have recently been considered for scale-up to commercial processes. One important chemical conversion, which is difficult to achieve enantio- or enantiotopo- selectively, is the Baeyer-Villiger (BV) oxidation of ketones. Using cyclohexanone monooxygenase to catalyse the reaction produces optically pure esters and lactones with exquisite enantiomeric excess values. Recently, these enzymes and their many applications in synthetic chemistry have been explored. The scale-up of these conversions has been examined with the idea of implementing the first commercial Baeyer-Villiger monooxygenase-based process. Here, we review the state-of-the-art situation for the scale-up and exploitation of these enzymes.

Microbial Transformations 16. One-step synthesis of a pivotal prostaglandin chiral synthon via a highly enantioselective microbiological Baeyer-Villiger type reaction

Abstract The bioconversion of bicyclo[3.2.0]hept-2-en-6-one is described. Each one of its enantiomers affords a different lactone via a highly regio and enantiospecific Baeyer-Villiger type process.

Preparative scale Baeyer-Villiger biooxidation at high concentration using recombinant Escherichia coli and in situ substrate feeding and product removal process

An efficient biocatalytic process based on the use of adsorbent resin (in situ substrate feeding and product removal) makes experiments at high substrate concentration possible by overcoming limitations due to substrate and product inhibition. This process was successfully applied to the preparative scale Baeyer–Villiger biooxidation of (−)-(1S,5R)-bicyclo[3.2.0]hept-2-en-6-one (25 g). Whole cells of recombinant E. coli (1 liter) overexpressing cyclohexanone monooxygenase were used as a biocatalyst and the substrate was preloaded onto the adsorbent resin. The corresponding lactone was obtained in 75–80% yield. Time for cell growth and biotransformation is about 24 h each and oxygen supply can be improved by using a tailor-made bubble column.

A chemoenzymatic strategy for the synthesis of enantiopure (R)-(−)-baclofen

Abstract A seven-step enantioselective synthesis of (R)-(−)-baclofen 1 is described. The strategy developed involved, as a key step, a microbiologically mediated Baeyer Villiger oxidation of the prochiral 3-(4′-chlorobenzyl)-cyclobutanone 3 which led to the optically pure (R)-(−)- 4 lactone. This was further transformed throughout chemospecific reactions into the target molecule (R)-(−)- 1 .

Microbiological transformations 36: Preparative scale synthesis of chiral thioacetal and thioketal sulfoxides using whole-cell biotransformations

Abstract This work describes the preparative scale enantioselective oxidation of some prochiral dithioacetals and dithioketals to their corresponding chiral monosulfoxides using whole-cell cultures of microorganisms.

Microbiological transformations. Part 51: The first example of a dynamic kinetic resolution process applied to a microbiological Baeyer–Villiger oxidation

Abstract The dynamic resolution of racemic 2-benzyloxymethylcyclopentanone 1 upon microbiologically mediated Baeyer–Villiger oxidation allowed the corresponding ( R )-lactone 2 to be prepared in 85% yield and 96% ee.

Microbiological transformations. 23. A surprising regioselectivity of microbiological Baeyer-Villiger oxidations of menthone and dihydrocarvone

Abstract Regioisomeric lactones (ee98%) were obtained by microbiological Baeyer-Villiger oxidation of enantiomers of menthone and dihydrocarvone. The regioselectivity of the biotransformation is shown to be dependant upon the considered enantiomer. An improvement of our empirical model of the active site is suggested.

CHEMOENZYMATIC SYNTHESIS OF MARINE BROWN ALGAE PHEROMONES

Abstract (+)-(3S,4S)-3-n-butyl-4-vinylcyclopent-l-ene 1, (+)-(Z)-(3S,4S)-Multifidene 2, (+)-(E)-(3S,4S)-Multifidene 3. (+)-(3R,4S)-Viridiene 4 and (+)-(2 R,3R,1′S,5′S)-Caudoxirene 5, constituents of various brown algae pheromones, were synthesized from racemic bicycloheptenone 7 via a novel microbiological Baeyer-Villiger oxidation performed using the fungus Cunninghamella echinulata. The total synthesis of these pheromone constituents was achieved by using, as a key step, a one-pot Swern oxidation and a Wittig or Julia-Lyhogoe olefination in order to perform the stereocontrolled construction of the C-3 (E) or (Z) double bond located on the side chain.

Asymmetric microbiological baeyer-villiger reaction of a bridged bicyclic ketone: divergent behaviour of its enantiomers

The biconversion of 7-anti-benzyloxymethylbicyclo[2.2.1]hept-5-en-2-one 1 with cells of Acinetobacter calcoaceticus NCIB 9871 has been studied. Its (1R,4S,7R) enantiomer underwent a Baeyer-Villiger oxidation yielding rearranged lactone 2 (ee 85%), whereas (1S,4R,7S)-1 was reduced to alcohols 3-endo (ee 95%) and 3-exo (o.p. 89%). Biotransformation of rac-1 by Acinetobacter calcoaceticus yielded the rearranged lactone (1S)-2 from (1R)-1 and the alcohols 3 from (1S)-1.

A short chemoenzymatic synthesis of (+)-multifidene and (+)-viridiene

(+)-Multifidene 1 and (+)-Viridiene 2, the major constituents of some brown algae pheromones, were synthesized in five steps from racemic bicycloheptenone 3via a novel microbiological Baeyer-Villiger oxidation.performed using the fungi Cunninghamella echinulata.